WO2018198101A2 - Procédé de préparation d'une forme cristalline d'éluxadoline - Google Patents
Procédé de préparation d'une forme cristalline d'éluxadoline Download PDFInfo
- Publication number
- WO2018198101A2 WO2018198101A2 PCT/IB2018/053134 IB2018053134W WO2018198101A2 WO 2018198101 A2 WO2018198101 A2 WO 2018198101A2 IB 2018053134 W IB2018053134 W IB 2018053134W WO 2018198101 A2 WO2018198101 A2 WO 2018198101A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- eluxadoline
- crystalline form
- reaction mass
- xrpd
- depicted
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
Definitions
- the present invention relates to processes for the preparation of a crystalline form of eluxadoline.
- Eluxadoline chemically is 5-[[[(25)-2-amino-3-[4-(aminocarbonyl)-2, 6- dimethylphenyl] - 1 -oxopropyl] [( 15)- 1 -(4-phenyl- lH-imidazol-2-yl)ethyl] amino] methyl] -2- methoxybenzoic acid, represented by Formula I.
- Eluxadoline is a mu-opioid receptor agonist, indicated in adults for the treatment of irritable bowel syndrome with diarrhea (IBS-D).
- U.S. Patent No. 7,741 ,356 describes a process for the preparation of eluxadoline.
- U.S. Patent Nos. 7,629,488 and 8,710,256 describe processes for the preparation of intermediates of eluxadoline.
- PCT Publication No. WO2009/009480 purportedly discloses forms alpha and beta crystals of eluxadoline and processes thereof.
- PCT Publication No. WO2009/009480 discloses that form alpha crystals can be prepared by storing the zwitterion of eluxadoline at 0-25% relative humidity (RH) for 3 days and form beta crystals can be prepared by storing the zwitterion of eluxadoline at greater than 60% RH for 3 days.
- RH relative humidity
- PCT Publication No. WO2017/015606 purportedly discloses amorphous form, crystalline forms I, II, III and IV, and processes for their preparation and a process for the preparation of form alpha crystal of eluxadoline. Summary of the Invention
- the present invention relates to processes for the preparation of a crystalline form of eluxadoline.
- Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline form of eluxadoline.
- Figure 2 depicts an X-Ray Powder Diffraction (XRPD) pattern of a crystalline form of eluxadoline.
- XRPD X-Ray Powder Diffraction
- room temperature refers to the temperature in the range of 25°C to 35°C.
- contacting refers to dissolving, slurrying, stirring, heating, suspending, or combinations thereof.
- reaction mass refers to suspension, solution, emulsion, or precipitate.
- a first aspect of the present invention provides a process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising contacting eluxadoline with a solvent.
- Eluxadoline used for the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be prepared by any method provided in the art, for example, the methods as disclosed U.S. Patent No. 7,741,356.
- solvents examples include methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
- the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 35°C to about 75°C.
- the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 35°C to about 70°C.
- the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 40°C to about 65°C.
- the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out at a temperature of about 45°C to 65°C.
- the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 4 hours to about 24 hours. In an embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 8 hours to about 22 hours. In another embodiment, the preparation of crystalline form of eluxadoline as depicted in Figure 1 is carried out for about 10 hours to about 18 hours. In another embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 12 hours to about 16 hours.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
- a second aspect of the present invention provides a process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising:
- reaction mass ii) heating the reaction mass at 35°C to 70°C followed by optional distillation of the solvent to obtain a reaction mass
- Eluxadoline used for the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be prepared by any method provided in the art, for example, the methods as disclosed U.S. Patent No. 7,741,356.
- solvents examples include methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
- the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 4 hours to about 24 hours. In an embodiment, the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 5 hours to about 22 hours.
- the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 10 hours to about 18 hours. In another embodiment, the preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 is carried out for about 12 hours to about 16 hours.
- reaction mass of step i) is treated with activated carbon.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
- a third aspect of the present invention provides a process for the preparation of a crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 comprising:
- reaction mass ii) heating the reaction mass followed by partial distillation of the solvent to obtain a reaction mass
- step iv) storing the crystalline form of step iii) at 25°C to 45°C and relative
- Eluxadoline used for the preparation of the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be prepared by any method provided in the art, for example, the methods as disclosed U.S. Patent No. 7,741,356.
- solvents include methanol, ethanol, iso-propyl alcohol, n-propyl alcohol, n-butanol, methyl iso-butyl ketone, acetone, dichloromethane, ethyl acetate or a mixture thereof.
- the heating of the reaction mass of step ii) is carried out at a temperature of about 35°C to 85°C. In an embodiment, the heating of the reaction mass of step ii) is carried out at a temperature of about 38°C to about 82°C.
- the partial distillation of the solvent of step ii) is carried out at a temperature of about 35°C to 85°C. In an embodiment, the partial distillation of the solvent of step ii) is carried out at a temperature of about 38°C to about 82°C.
- the crystalline form of step iii) is stored for about 1 day to about 7 days. In an embodiment, the crystalline form of step iii) is stored for about 3 days to about 5 days.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may optionally be isolated by filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
- the crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1 may be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, suck drying, air drying, or agitated thin film drying.
- XRPD of the samples was determined by using a PANalytical ® instrument; Model X'pert PRO; Detector: X'celerator ® .
- Example 1 Preparation of crystalline form of eluxadoline characterized by XRPD as depicted in Figure 1
- Method A Eluxadoline (10 g) was added to iso-propyl alcohol (300 mL) at 55°C to obtain a reaction mass. The reaction mass was then heated to 60°C to obtain a suspension. The suspension was stirred for 5 hours at 60°C to 66°C, and then cooled to 25°C. The product was filtered, suck dried for 5 minutes and then washed with isopropyl alcohol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method B Eluxadoline (10 g) was added to n-propyl alcohol (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 5 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with n-propyl alcohol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method C Eluxadoline (10 g) was added to methyl isobutyl ketone (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with methyl isobutyl ketone (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method D Eluxadoline (10 g) was added to ethyl acetate (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with ethyl acetate (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method F Eluxadoline (10 g) was added to n-butanol (300 mL) at 55°C to obtain a reaction mass. The reaction mass was heated to 60°C to obtain a suspension. The suspension was stirred for 22 hours at 60°C to 65 °C and then cooled to 25 °C. The product was filtered, suck dried for 5 minutes and then washed with n-butanol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method G Eluxadoline (10 g) was added to a mixture of n-propyl alcohol (300 mL) and dichloromethane (400 mL) at 35°C to 38°C to obtain a reaction mass. The reaction mass was heated to 38°C to 40°C to obtain a suspension and then distilled up to a volume of 300 mL at 38°C to 42°C. The suspension was stirred for 3 hours at 50°C to 55°C and then cooled to 25 °C. The product obtained was filtered, and then washed with n-propyl alcohol (20 mL) to obtain a solid. The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- Method H Eluxadoline (20 g) was added to a mixture of n-propyl alcohol (10 mL) and methanol (800 mL) at 40°C to 45°C and then stirred for 5 minutes to obtain a clear solution. The solution was filtered through Hyflo® and then washed with methanol (40 mL). The filtrate was heated at 60°C to 65 °C and then distilled up to a volume of 200 mL at 60°C to 65 °C to obtain a suspension. The suspension was stirred for 4 hours at 60°C to 65 °C and then cooled to 5°C to 10°C. The product obtained was filtered and then washed with methanol (40 mL) to obtain a solid. The solid obtained was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
- the suspension was stirred for 4 hours to 5 hours at 60°C to 65°C and then cooled to 0°C to 5°C.
- the product obtained was filtered and then washed with methanol (160 mL) to obtain a solid.
- the solid was suck dried for 5 minutes and then dried under vacuum at 55°C to 60°C for 15 hours to obtain the title compound.
- Method I Eluxadoline (10 g) was added to isopropyl alcohol (1200 mL) at 72°C to obtain a reaction mass. The reaction mass was heated to 82°C and then distilled up to a volume of 100 mL at 80°C to 82°C to obtain a suspension. The suspension was stirred for 4 hours at 80°C to 82°C and then cooled to 30°C. The product obtained was filtered, suck dried for 5 minutes and then washed with isopropyl alcohol (20 mL). The solid obtained was suck dried for 5 minutes and then dried under vacuum at 60°C to 65 °C for 12 hours. The solid (2.0 g) was stored at 25 ⁇ 2°C/60 ⁇ 5% RH for 3 days and then further dried under vacuum at 55°C to 60°C for 12 hours to obtain the title compound.
Abstract
La présente invention concerne des procédés de préparation d'une forme cristalline d'éluxadoline.
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IN201711014592 | 2017-04-25 | ||
IN201711014592 | 2017-04-25 |
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WO2018198101A3 WO2018198101A3 (fr) | 2019-05-16 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10314819B2 (en) | 2015-07-23 | 2019-06-11 | Teva Pharmaceuticals International Gmbh | Solid state forms of Eluxadoline |
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KR101690161B1 (ko) * | 2007-07-09 | 2016-12-27 | 퓨리엑스 파마슈티컬스, 인코포레이티드 | 신규한 결정 및 5-({[2-아미노-3-(4-카르바모일-2,6-다이메틸-페닐)-프로피오닐]-[1-(4-페닐-1h-이미다졸-2-일)-에틸]-아미노}-메틸)-2-메톡시-벤조산의 제조 방법 |
IS2977B (is) * | 2015-02-23 | 2017-07-15 | Actavis Group Ptc Ehf. | Aðferð til framleiðslu á milliefnum sem eru nytsamleg við nýsmíði á elúxadólíni |
US10314819B2 (en) * | 2015-07-23 | 2019-06-11 | Teva Pharmaceuticals International Gmbh | Solid state forms of Eluxadoline |
EP3272741A1 (fr) * | 2016-07-21 | 2018-01-24 | Euticals S.P.A. | Nouvelles formes cristallines de solvate stable d'eluxadoline |
WO2017221213A1 (fr) * | 2016-06-23 | 2017-12-28 | Sun Pharmaceutical Industries Limited | Méthodes de préparation d'oxazoldinone. |
CZ2016548A3 (cs) * | 2016-09-07 | 2018-03-14 | Zentiva, K.S. | Pevné formy eluxadolinu |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US10314819B2 (en) | 2015-07-23 | 2019-06-11 | Teva Pharmaceuticals International Gmbh | Solid state forms of Eluxadoline |
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